Digoxin, digitalis and related cardiotonic agents act on the heart in a variety of ways resulting in an increase in the force of contraction (a positive inotropic effect), a slowing in the rate of atrioventricular conduction thereby leading to improved hemodynamics and renal function. Such agents are useful in treating congestive heart disease and atrial fibrillation.
Congestive heart disease is characterized by an incomplete emptying of blood from the heart during ventricular contraction, which leads to an enlargement of the heart. When congestive heart disease is treated with cardiac glycosides there is a reduction of heart rate, a more complete filling of the ventricules, and the size of the heart decreases and begins to return to normal. Atrial fibrillation is a condition in which the atria contract much more often then the ventricules, causing the lower heart chambers to be bombarded by impulses. The ventricules respond by weakly and inefficiently contracting. When used to treat atrial fibrillation, cardiac glycosides depress the conduction rate, slowing the rate of ventricular contraction and reestablishing a synchronous and effective heart beat.
One of the drawbacks of digoxin and related cardiotonic agents is their low therapeutic index. There is a narrow window of concentrations in which the drugs are effective for the treatment of congestive heart failure or atrial fibrillation. In addition, there are numerous adverse side effects resulting from therapy with digoxin and related compounds. These have been extensively reviewed by T. B. Smith et al. in Prog. Cardivas. Dis. 26:21-56, 1984. Side effects of digoxin therapy include impotence, weakness and depression. A further drawback is that some patients do not respond to digoxin treatment. Furthermore, digoxin and digitalis are only effective to depress blood pressure in patients that have previously suffered congestive heart failure and are ineffective in normal hypertensive patients.
Hypertension is a common condition and is characterized by elevations of atrial pressure which could result in secondary organ damage and a reduced life span. The condition is currently treated using four general classes of drugs: diuretics, anti-adrenergic agents, vasodialtors and angiotensin blockers (Harrison's Principles of Internal Medicine, K. J. Issel Bacher et al., eds., pp. 1172-1176, McGraw Hill, New York, 1980). Each of these agents produce side effects and their use is limited. Cardiac glycosides, used to treat congestive heart disease, are essentially ineffective in treating hypertension.
Numerous investigators have reported the existence of endogenous digoxin-like factors isolated from various biological fluids. For example, Tymiak, A. K. et al. (Proc. Nat. Acad. Sci. USA 9:8189-8193, 1993) disclosed a ouabain-like agent isolated from bovine hypothalamus. Goto, A. et al. (Clin. Chem 36:161-162, 1992) also reported finding a ouabain-like factor in human urine and bovine plasma. Shaikh, I. M. et al. (J. Biol. Chem. 2:13972-13978, 1991) disclosed a digoxin-like immunoreactive factor isolated from mammalian adrenal cortex. The factor was said to have a molecular mass of 780 daltons comprised of a 390 dalton aglycone component plus several sugar moieties.
U.S. Pat. Nos. 5,028,438 and 5,122,371 issued Jul. 2, 1991 and Jun. 6, 1992, respectively, describe a biologically active agent having hypotensive activity in mammals. The agent was said to be derived from Type 1 human female breast cyst fluid and to be immunoreactive with digoxin antibodies.